Mathematical models and hepatology; oil and vinegar?

Mathematical models are increasingly being used in medicine to study physiological, pathophysiological and therapeutic pathways [1–3]. In hepatology, mathematical abstractions have been beneficial to predict the viral load of hepatitis C following treatment [4], outcome after acetaminophen overdose [5], or to quantify porto-systemic shunting and inter-organ ammonia metabolism at different stages of cirrhosis [6]. However, in many medical fields (including hepatology), there is much resistance to include theoretical models in their traditional tool set and furthermore a lack of confidence in the generated theoretical results

Ammonia : this is not the end but rather the end of the beginning

Hepatic encephalopathy (HE) represents a wide spectrum of neurological or neuropsychological symptoms caused by liver disease and/or portosystemic shunts. The major role of hyperammonemia in association with systemic inflammation and oxidative stress in the pathogenesis of HE has progressively emerged. However, the cascading downstream effects caused by these pathogenic factors remain unresolved. The underlying abnormalities which are thought to cause HE include modification of glutamatergic and GABAergic neurotransmission, mitochondrial dysfunction, energy impairment, lactate dyshomeostasis, increased blood-brain barrier permeability, brain edema/astrocyte swelling, as well as accumulation of toxic compounds (manganese, bile acids, indols)

Targeting the muscle for the treatment and prevention of hepatic encephalopathy

Muscle mass loss or sarcopenia is a principle component of malnutrition which prevails in 65–90% of patients with end-stage liver disease [1]. Intuitively, the roots of malnutrition play a precipitating role in muscle catabolism. Undernutrition frequently occurs in cirrhosis since an inadequate diet is compounded by a hypermetabolic energy demand. However, multiple other factors contribute to the pathogenesis of malnutrition including malabsorption of nutrients, metabolic alterations, increased intestinal protein losses, reduced protein synthesis, increased protein catabolism and disturbance of substrate utilization [2,3]

Astrocyte glutamine synthetase : pivotal in health and disease

The multifunctional properties of astrocytes signify their importance in brain physiology and neurological function. In addition to defining the brain architecture, astrocytes are primary elements of brain ion, pH and neurotransmitter homoeostasis. GS (glutamine synthetase), which catalyses the ATP-dependent condensation of ammonia and glutamate to form glutamine, is an enzyme particularly found in astrocytes. GS plays a pivotal role in glutamate and glutamine homoeostasis, orchestrating astrocyte glutamate uptake/release and the glutamate-glutamine cycle. Furthermore, astrocytes bear the brunt of clearing ammonia in the brain, preventing neurotoxicity. The present review depicts the central function of astrocytes, concentrating on the importance of GS in glutamate/glutamine metabolism and ammonia detoxification in health and disease

Capacity of Molecular Channels with Imperfect Particle-Intensity Modulation and Detection

This work introduces the particle-intensity channel (PIC) as a model for molecular communication systems and characterizes the properties of the optimal input distribution and the capacity limits for this system. In the PIC, the transmitter encodes information, in symbols of a given duration, based on the number of particles released, and the receiver detects and decodes the message based on the number of particles detected during the symbol interval. In this channel, the transmitter may be unable to control precisely the number of particles released, and the receiver may not detect all the particles that arrive. We demonstrate that the optimal input distribution for this channel always has mass points at zero and the maximum number of particles that can be released. We then consider diffusive particle transport, derive the capacity expression when the input distribution is binary, and show conditions under which the binary input is capacity-achieving. In particular, we demonstrate that when the transmitter cannot generate particles at a high rate, the optimal input distribution is binary.Comment: Accepted at IEEE International Symposium on Information Theory (ISIT

Increased extracellular brain glutamate in acute liver failure: decreased uptake or increased release?

Glutamatergic dysfunction has been suggested to play an important role in the pathogenesis of hepatic encephalopathy (HE) in acute liver failure (ALF). Increased extracellular brain glutamate concentrations have consistently been described in different experimental animal models of ALF and in patients with increased intracranial pressure due to ALF. High brain ammonia levels remain the leading candidate in the pathogenesis of HE in ALF and studies have demonstrated a correlation between ammonia and increased concentrations of extracellular brain glutamate both clinically and in experimental animal models of ALE Inhibition of glutamate uptake or increased glutamate release from neurons and/or astrocytes could cause an increase in extracellular glutamate. This review analyses the effect of ammonia on glutamate release from (and uptake into) both neurons and astrocytes and how these pathophysiological mechanisms may be involved in the pathogenesis of HE in ALF